Cyclic GMP (cGMP) is the primary intracellular messenger for vision and retinal photoreceptors. The cGMP is regulated by a retinal phosphodiesterase (PDE), and the focus of this application is to study, in detail, the biochemistry of the regulation of PDE activity. The specific aims of the application are: (1) to study conformational changes of rod PDE structure upon binding of cGMP or its inhibitory gamma subunit; (2) to determine whether novel pathways distinct from transducin activation/inactivation regulate rod PDE during recovery or adaptation; (3) to identify the determinants at the catalytic site of rod and cone PDE responsible for binding cyclic nucleotide substrates or pharmacological inhibitors of the enzyme; and (4) to test the idea that physiological differences in rod and cone responsiveness can be ascribed in part to differences in the activation and regulation of the distinct isoform of PDE found in cone photoreceptors.